It is planned to examine the possible rate limiting reactions in gluconeogenesis and ketogenesis under various physiological states. These various states will be produced by the use of diets and/or hormones. The use of isolated liver cells techniques will be used in conjunction with various substrates or combination of substrates to ascertain which reactions may be rate limiting under each of these conditions. The relationship of gluconeogenesis and ketogenesis will also be examined under these various conditions to see if this relationship, as occurs in starvation and diabetes, is correlated in many other states. The possibility of metabolic compartmentalization, in addition to sub-cellular organelle compartmentalization, in the liver will also be examined. We are examining the role of lactate and ornithine as well as enzyme activity as controlling factors in urea synthesis. The properties of transport and synthetic capacity are being examined particularly in regards to ornithine, citrulline, and arginine. The effects of hormones on urea synthesis are also being examined with the isolated liver cells. The correlation between productive capacity and enzymic metabolic potential is being examined. A study of arginine metabolism and the urea cycle particularly in regards to the in vivo synthesis of arginine and its role in metabolism such as protein synthesis and urea synthesis. The control of urea synthesis by liver cells is also being investigated. These factors will include effects of diet and hormones on permeability of arginine in the liver as well as potential rate of arginine synthesis by the body. BIBLIOGRAPHIC REFERENCES: Relative Importance of the Two Major Pathways for the Conversion of Cysteine to Glucose in the Perfused Rat Liver. R.C. Simpson and R.A. Freedland. J.Nutr. 105, 1440-1446, 1975. Effects of Glucagon on Gluconeogenesis from Lactate and Propionate in the Perfused Rat Liver. T.C. Chan and R.A. Freedland. Proc. Soc. Exp. Biol. and Med. 151, 372-375, 1976.